The utilization of ozone for external medical applications by Gérard V. Sunnen, M.D. May 1998

Ozone, an allotropic form of oxygen, possesses unique properties which are being defined and applied to biological systems as well as to clinical practice. As a molecule containing a large excess of energy, ozone, through incompletely understood mechanisms, manifests bactericidal, virucidal, and fungicidal actions which may make it a treatment of choice in certain conditions and an adjunct to treatment in others.

The oxygen atom exists in nature in several forms: (1) As a free atomic particle (0), it is highly reactive and unstable. (2) Oxygen (02), its most common and stable form, is colorless as a gas and pale blue as a liquid. (3) Ozone (03), has a molecular weight of 48, a density one and a half times that of oxygen, and contains a large excess of energy in its molecule (03 -> 3/2 02 + 143KJ/mole). It has a bond angle of 127 ± 3, resonates among several forms, is distinctly blue as a gas, and dark blue as a solid. (4) 04 is a very unstable, rare, nonmagnetic pale blue gas, which readily breaks down into two molecules of oxygen.

Ozone is a powerful oxidant, surpassed in this regard only by fluorine. Exposing ozone to organic molecules containing double or triple bonds yields many complex and as yet incompletely configurated transitional compounds (i.e. zwitterions, molozonides, cyclic ozonides), which may be hydrolysed, oxidized, reduced, or thermally decomposed to a variety of substances, chiefly aldehydes, ketones, acids or alcohols. Ozone also reacts with saturated hydrocarbons, amines, sulfhydryl groups, and aromatic compounds.

Importantly relevant to biological systems is ozone's interaction with tissue--including blood--constituents. The most studied is lipid peroxidation, although interactions have yet to be more fully investigated with complex carbohydrates, proteins, glycoproteins, and sphingolipids.
WHY OZONE IS A DRUG.

Ozone is a pan-virucidal, and a pan-bactericidal agent. In addition, it is well documented that many species of fungi are inactivated by its actions, as well as several types of protozoa.

Ozone is a gas which, properly interfaced with biological systems or pathologically afflicted tissues, exerts significant therapeutic activity. As is the case with many medications, however, ozone has a range of therapeutic action which, in the terminology of pharmacokinetics, is termed a therapeutic window. Indeed, ozone applied in concentrations that are too low, has little therapeutic effect. More importantly, when it is applied in too high concentrations, it is known to have some toxic sequelae.

Due to ozone's demarcated therapeutic range, ozone concentrations administered to the patient need to be carefully calibrated and controlled. The therapeutic ozone/oxygen mixture requires state of the art quantitative (dosage, concentration), as well as qualitative (purity) controls, which can only be provided by an appropriate contemporary technology.

At room temperature, approximately 50% of ozone reverts to pure oxygen. This adds an important dimension to the calculation of the amount of ozone administered. As regards the generation and delivery system, of foremost importance is the oxygen source which must be of medical grade purity, and thus devoid of nitrogen or impurities. The presence of nitrogen favors the production of nitrogen oxides which are tissue-toxic. Due to these considerations, ozone needs to be conceptualized as a medication with complex therapeutic dynamics, which need to be carefully considered and evaluated in relation to the particular medical conditions being treated.

METHODS OF OZONE GENERATION AND ADMINISTRATION

Ozone generation and delivery systems are intrinsically connected to the fact that ozone, utilized for human or veterinary therapeutic purposes, requires that it be created at the moment it is to be administered. Ozone, in this sense is not a drug that has a shelf life, and that can be kept for long periods of time at a certain determined dosage. As a gas with a half life of approximately one hour at room temperatures, the gauging of ozone's dosage is intrinsically connected to the sophistication of its manufacture technology and its pharmacodynamics.

Ideally, the treating clinician should be able to be informed of the exact concentration of the ozone drug being generated and delivered (i.e., a digital readout of ozone output in micrograms per milliliter, or grams per cubic meter). In addition, the clinician needs to factor the natural and constant conversion of ozone into oxygen, so as to arrive at precise measurements of dosage in relation to duration of administration.

In the case of external application, the ozone generator supplies a dosage of ozone/oxygen determined by the clinician to be therapeutically indicated. This, in practice, may involve an infected foot, a post-surgical incision, an area afflicted by a burn, a decubitus ulcer, or a poorly healing post-traumatic wound.

In the practice of external ozone application, a specially designed polyester envelope is used to enclose the area under treatment. A precise fitting of the bag is needed in order to ensure (I) A proper constant concentration of delivered ozone, (2) A suitable containment of ozone/oxygen to the affected area. This guarantees that ozone will be prevented from escaping into the ambient environment which, in higher concentrations, may lead to respiratory epithelial irritation in the patient or in the treating personnel, and (3) An opportunity for the precise timing of the duration of ozone exposure under controlled conditions.

In order to respect proper environmental controls, and to prevent ozone from diffusing into the treatment space, an exit catheter connected to the polyethelene envelope is directed to the ozone generator for catalytic reconversion to oxygen.
Externally applied ozone concentrations need to be carefully adjusted. The clinician must be able to gauge the proper ozone concentration geared to the specific medical condition under treatment. In wet burns, for example, initial ozone concentrations will need to be low, in order to prevent inordinate systemic absorption. As the burn heals, and progressively dries, greater ozone concentrations may then be administered in order to keep pace with the rate of healing.

THE EFFECTS OF OZONE ON PATHOGENS

The antipathogenic effects of ozone have been substantiated for several decades. Its killing action upon bacteria, viruses, fungi, and in many species of protozoa, serve as the basis for its increasing use in disinfecting municipal water supplies in cities worldwide.

The mechanisms of ozone bacterial destruction need to be further elucidated. It is known that the cell envelopes of bacteria are made of polysaccharides and proteins, and that in Gram negative organisms, fatty acid alkyl chains and helical lipoproteins are present. In acid-fast bacteria, such as Mycobacterium tuberculosis, one third to one half of the capsule is formed of complex lipids (esterified mycolic acid, in addition to normal fatty acids), and glycolipids (sulfolipids, lipopolysaccharides, mycosides, trehalose mycolates). The high lipid content of the cell walls of these ubiquitous bacteria may explain their sensitivity, and eventual demise, subsequent to ozone exposure. Ozone may also penetrate the cellular envelope, directly affecting cytoplasmic integrity, disrupting any one of numerous levels of its metabolic complexities.

Numerous families of viruses including poliovirus I and 2, human rotaviruses, Norwalk virus, Parvoviruses, and Hepatitis A, B, and non-A non-B (C), among many others, are susceptible to the virucidal actions of ozone.

Most research efforts on ozone's virucidal effects have centered upon ozone's propensity to break apart lipid molecules at sites of multiple bond configuration. Indeed, once the lipid envelope of the virus is fragmented, its DNA or RNA core cannot survive.

Non-enveloped viruses (Adenoviridae, Picornaviridae, namely poliovirus, Coxsachie, Echovirus, Rhinovirus, Hepatitis A and E, and Reoviridae (Rotavirus), have also begun to be studied. Viruses that do not have an envelope are called "naked viruses." They are constituted of a nucleic acid core (made of DNA or RNA) and a nucleic acid coat, or capsid, made of protein. Ozone, however, aside from its well recognized action upon unsaturated lipids, can also interact with certain proteins and their constituents, namely amino acids. Indeed, when ozone comes in contact with capsid proteins, protein hydroxides and protein hydroperoxides are formed.

Viruses have no protection against oxidative stress. Normal mammalian cells, on the other hand possess complex systems of enzymes (i.e., superoxide dismutase, catalase, peroxidase) which tend to ward off the nefarious effects of free radical species and oxidative challenge. It may thus be possible to treat infected tissues with ozone, respecting the homeostasis derived from their natural defenses, while neutralizing offending and attacking pathogen devoid of similar defenses.

The enveloped viruses are usually more sensitive to physico-chemical challenges than are naked virions. Although ozone's effects upon unsaturated lipids is one of its best documented biochemical action, ozone is known to interact with proteins, carbohydrates, and nucleic acids. This becomes especially relevant when ozone inactivation of non-enveloped virions is considered.

Fungi families inhibited and destroyed by exposure to ozone include Candida, Aspergilus, Histoplasma, Actinomycoses, and Cryptococcus. The cell walls of fungi are multilayered and are composed of approximately 80% carbohydrates and 10% of proteins and glycoproteins. The presence of many disulfide bonds has been noted, making this a possible site for oxidative inactivation by ozone.

In all likelihood, however, ozone has the capacity to diffuse through the fungal wall into the organismic cytoplasm, thus disrupting cellular organelles.
Protozoan organisms disrupted by ozone include Giardia, Cryptosporidium, and free-living amoebas, namely Acanthamoeba, Hartmonella, and Negleria. The exact mechanism through which ozone exerts anti-protozoal action has yet to be elucidated.

CUTANEOUS PHYSIOLOGICAL EFFECTS OF OZONE

The positive effects of oxygenation of many dermatological conditions has long been established, and forms the basis for the use of hyperbaric oxygen treatment. Oxygen has the capacity to diffuse into the tissues, inhibit the growth of anaerobic bacteria, and raise the local oxygen content of treated tissues, thus alleviating their oxygen deprivation.

Ozone, however, as an added ingredient, has properties which clearly transcend oxygen administration alone. The two properties invoked are (I) A much broader range of pathogen killing action, and (2) A vasodilatation of arterioles, stimulating greater blood flow to tissues, with all its attendant benefits, including the greater availabilities of nutrients and of the component of vital immunological adaptations and defenses.

EXTERNAL MEDICAL CONDITIONS BENEFITED BY OZONE THERAPY

In view of the above-mentioned principles of external ozone/oxygen applications, we may list the following common conditions to be beneficially influenced by this unique drug therapy, utilized either in conjunction with other modalities, or used alone:

INFECTED WOUNDS

This category of wound has, by definition, not yet reached the status of chronicity due to a combination of circulatory compromise and infective onslaughts. In fact, this category of wound may simply be post-surgical, and only potentially prone to infection.

The use of topical ozone therapy in these cases may be solely preventive, and aimed at improving circulation on one hand, and inhibiting the proliferation of potentially infective organisms on the other.

POORLY HEALING WOUNDS

Wounds which heal in an indolent manner are frustratingly difficult to master. Some of these wounds, are apt to regress, thus encouraging therapeutic strategies to become more aggressive, even experimental, but not necessarily effective.

Generally speaking, poorly healing wounds owe their definition by the chronicity of their healing, which is most commonly caused by the types and mixed variety of offending organisms they harbor.

Living organisms are constantly in contact with pathogens which, under the proper conditions, are able to parasitically proliferate to create pathological conditions. Many different types of pathogens may be involved, spanning a large spectrum of infective diversity:

Anaerobic bacteria--bacteria that do not need oxygen for their proliferation (i.e. Bacteroides, Clostridium, Streptococci), maybe noxiously active at deeper levels of the dermis, insulated to the healing influence of oxygen. Anaerobic bacteria are responsible for many devastating infections, which are generically subsumed under the appellation of gangrene. Aerobic bacteria, on the other hand, are closely identified with superficial epidermal layers; yet, when the latter are broken down, they may become influential in infective processes (i.e., Staphylococcus epidermis, Corynebacteria, Propionobacteria).

DECUBITUS ULCERS

This common condition arises when a patient stays in bed, or in a wheelchair, in one position for a prolonged period of time. The pressure exerted upon the skin contact points compresses the dermal arterioles preventing proper perfusion of tissues. This leads to the oxygen starvation of tissues, impaired skin resilience, then to eventual breakdown of the skin itself. An ulcer develops, which may become quite large and usually infected with a spectrum of pathogenic organisms. At times the breakdown is so severe and the denudation of skin tissues so complete that the bottom of the ulcer reaches the bone and osteomyelitis begins.

The treatment of decubitus ulcers requires a multidisciplinary approach, including surgical, topical, and mechanico-physiological interventions. Topical antibiotics often fail to penetrate the wound and not infrequently cause secondary dermatitis in their own right.

Aside from the benefits of topical ozone therapy enunciated in this text, it should be mentioned that an added therapeutic feature of ozone, especially as it relates to the treatment of deep ulcers, is its capability to penetrate to deeper tissue level, thereby affecting pathogens which would normally be protected by tissue overlay.

CIRCULATORY DISORDERS

This extremely common class of disorders have one common denominator, namely impaired circulation to tissues via compromise of vascular patency and integrity. A prototypic disease showing this phenomenon is diabetes. Diabetes is a complex disease which manifests both vascular disturbances to many organ systems (i.e. retina, kidney, peripheral nerves), and, in addition, disturbances to carbohydrate metabolism.

In cases where diabetes affects the peripheral circulation, tissues such as the epidermis and dermis become vascularly compromised, and thus are more prone to injuries and recalcitrant infections.

Diabetic ulcers frequently develop following simple abrasions, contusions, and lacerations. These ulcers, not unlike decubitus ulcers, are notoriously difficult to treat, and are apt to be chronically treated with topical creams and ointments, which can only address the viability of a minor proportion of putative infectious organisms. These organisms may easily develop resistance to these therapeutic agents. Concurrently, pathogens resistant to these therapies continue to proliferate and to aggravate the condition.

Arteriosclerosis is a condition marked by the thickening and hardening of all arterial conduits in the body. The normal pliability and patency of blood vessels is compromised, leading to disturbed circulation to many organ systems. In the case of impaired peripheral circulation (Arteriosclerosis obliterans), skin disorders may develop which include trophic changes (dry hair, shiny skin), apt to injury and eventual ulcer formation. As in the case with diabetic ulcers, these circumstances often invite multi-pathogenic infections.

LYMPHATIC DISEASES

The lymphatic system is essential for proper fluid equilibration within the body, and most importantly for adequate defense against infections.
Lymphedema is a condition caused by blockage to lymphatic drainage. It may be secondary to trauma, surgical procedures, and infections (i.e. streptococcal cellulitis, filiriasis, lymphogranuloma venereum).

Increasingly common is lymphedema resulting from surgical removal of lymph nodes following surgery for breast cancer. The affected arm in these patients is likely to be chronically swollen, and exercises are often prescribed to develop collateral circulation. Most importantly, however, is the occurrence of infections following even minor injuries to the arm. Injuries are then much more apt to become infected due to the absence of lymphatic system defenses. In these cases intensive topical wound care is resorted to and systemic antibiotic treatment is often prescribed.

Topical ozone treatment applied as soon as injury is noted in the affected hand or arm may prevent secondary infection, lymphedema, and the use of topical and/or systemic antibiotics.

FUNGAL SKIN INFECTIONS

Fungi are present on human skin in a quasi symbiotic relationship. Candida, Aspergillus, Histoplasma, are often found on intact skin, without causing clinical problems.

However, under certain conditions, the normal balance of the dermis is disturbed, allowing superficial fungi to proliferate. Tinea capitis is manifested by pustular eruptions of the scalp, with scaling and bald patches. Tinea cruris is a fungal pruritic dermatitis in the inguinal region.

Thermal burns are divided into first, second, and third degrees, depending upon the depth of tissue damage. First degree burns are superficial, and include erythema, swelling, and pain. In second degree burns, the epidermis and some portion of the underlying dermis are damaged, leading to blister and ulcer formation. Healing occurs in one to three weeks, usually leading to little or no scar formation.

In third degree burns, muscle tissue and bone may be involved, and secondary infection is very common.

It is in cases marked by significant tissue injury, and especially in cases involving infections, that topical ozone therapy finds the most usefulness. In the case of burns, the range of pathogenic organisms may be extremely wide (see the section on poorly healing wounds), and thus may be ideally suited for ozone therapy.

GENERAL VIRAL CONDITIONS WITH REFERENCE TO CUTANEOUS AFFLICTIONS

Ozone is actively virucidal to a staggering number of viral families. Most clearly documented are ozone's neutralizing effects upon lipidenveloped virions. These include diverse viral groups as the Hepadnaviridae (Hepatitis B and C), the Retroviridae (HIV-I and HIV-II), the Herpesviridae (Herpes simplex I and II, Cytomegalovirus, Epstein-Barr), Filoviridae (Ebola virus and Marburg virus), Orthomyxoviridae (Influenza A and B ), the Paramyxoviridae (Measles, Mumps, Parainfluenza, Respiratory syncytial virus), the Coranoviridae, the Togaviridae (Rubella, Eastern and Western equine encephalitis), and the Rhabdoviridae (Rabies).

Although lipid-enveloped viruses appear to be most susceptible to ozone inactivation due to their dependency on their outer lipid sheath, non-enveloped viruses are also negatively subject to ozone through its ability to interact with proteins, amino acids, carbohydrates and glycoproteins.

Herpes simplex viruses are extremely widespread in the human population. Two distinct types of viruses are known, namely Herpes simplex type I and II. Type I is transmitted via contact through mucosa or broken skin (often through saliva), while type II is more specifically sexually propagated.

In herpetic lesions, fluid accumulates between the dermis and epidermis, producing vesicles which rupture, thus releasing more virions. They then become easily infected by secondary organisms.

Herpes lesions have been extensively studied with reference to topical ozone administration. Ozone in these cases (I) Directly inactivated herpes viruses which are lipid-enveloped (2) Act as a pan-bactericidal agent in cases involving secondary infections, and (3) Promotes healing of tissues through circulatory enhancement. It is also postulated that ozone may have beneficial effects upon the peripheral neurons which harbor these viruses.

NAIL AFFLICTIONS

Afflictions implicating nails which are therapeutically assisted by topical ozone treatment include the following:

1. Candida albicans. Nails in this condition are painful, with swelling of the nail fold, and often, thickening and transverse grooving of the nail architecture. Loss of the nail itself is not infrequent. Another frequent condition is Tinea Unguium, marked by thickened, hypertrophic, and dystrophic toenails. There are currently no antifungal agents of proven efficacy for this condition.

2. Tinea Pedis (Athlete's Foot). This very common disorder is caused by infection with species of Trichophyton, and with Epidermophyton floccosum. Chronic infection involving the webbing of the toes may evolve to secondary bacterial involvement. Lymphangitis and lymphadenitis may present themselves, as well as infection of the nails themselves (Tinea unguium, Onychomycosis). Nails may become thickened, yellow, and brittle. The patient may then develop allergic hypersensitivity to these organisms which may manifest in other parts of their bodies.

Topical ozone therapy offers unique treatment opportunities to these recalcitrant infections. Ozone penetrates the affected areas, including the nails proper, and with repeated administration, is capable of inactivating all species of fungi mentioned above.

This condition occurs during times when the body is exposed to ionizing radiation. This may occur during an accident, or within the course of radiation therapy. Radiation energy is imparted to individual cells, leading to alteration in cellular DNA, thus favoring cellular injury and/or death.

Clinical findings are commensurate with the type, amount, and duration of radiation exposure. Several clinical syndromes have been delineated, including Radiation Erythema, Acute Radiodermatitis, and Chronic Radiodermatitis.

While DNA damage cannot be easily repaired (except perhaps partially through nutritional avenues such as vitamin E), secondary infections made more likely by decreased tissue resistance, may be countered by topical ozone therapy. This avoids the systemic absorption of topical creams and ointments, and ensures pan-pathogen protection.

FROSTBITE

Factors contributing to skin injuries due to cold derive from vasoconstriction and the formation of ice crystals within tissues. As frostbite progresses, loss of sensation occurs, and tissues become increasingly hard to the touch. Depending upon length of exposure and processes related to rewarming, dry gangrene may develop. Dry gangrene may evolve to wet gangrene if infection occurs.

Topical ozone therapy has proven to be effective in decelerating or halting the pathogenesis of frostbite through

(I) The immediate oxygenation of tissues,

(2) Increasing blood flow through a direct vasodilatory effect upon the dermal arterioles, and

(3) The prevention of secondary infection.

ADVANTAGES OF TOPICAL OZONE THERAPY

Topical ozone therapy for the disorders mentioned above requires sophisticated medical diagnosis of the underlying conditions, and an appropriately tailored treatment plan, which may include any one of several therapeutic modalities utilized concomitantly, including ozone, or may call for the utilization of ozone as the sole therapeutic intervention.

The salient advantages of topical ozone therapy include:

1. The ease of administration of this therapy, taking into consideration the strict parameters of the technology-to-drug symbiosis.

2. Ozone is an effective antagonist to the viability of an enormous range of pathogenic organisms. In this regard, ozone cannot be equaled. It is effective in inactivating anaerobic and aerobic bacterial organisms, a wide spectrum of viral particles--lipid as well as non-lipid enveloped--and a substantial spectrum of fungal and protozoal pathogens.
To replicate this therapeutic action, the medical conditions in question would have to be treated with a conglomeration of antibiotic agents, systemically and/or topically applied. This would present, in the context of contemporary medical practice, massive clinical difficulties.

3. Ozone therapy, appropriately applied in a timely fashion, may obviate the need for systemic anti-pathogen therapy, thus saving the patient from all the side effects and organ stresses this option could entail.

4. Ozone exerts its anti pan-pathonegic actions through entirely different mechanisms than conventional antibiotic agents. The latter must be constantly upgraded to surmount pathogen resistance and mutational defenses. Ozone, on the other hand, presents direct oxidative challenge which cannot, by all available pathogen defenses cannot be circumvented.

Ozone presents many features that are common to many drugs, namely a therapeutic window demarcated by sub-optimal dosage on one hand, and toxic higher dose levels on the other. For this reason ozone dosage must be carefully calibrated and delivered, a feasibility which has only currently been achieved through advances in contemporary technology.

Ozone is a pan-bactericidal, pan-virucidal, anti-fungal and antiprotozoan therapeutic agent which, utilized under treatment protocols which continue to need proper delineation through research, promises to become a potent adjunct to current medical treatment. It is also likely to show promise as a drug used as a sole therapeutic agent in our global growing need to bolster our antipathogen armamentarium.